Study Questions:

What is the impact of bradycardia and atrial fibrillation (AF) on cardiovascular outcomes among patients with coronary artery disease (CAD) treated with ivabradine?

Methods:

In the SIGNIFY (Study assessInG the morbidity–mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) study, patients with stable CAD (n = 19,083) were randomized to either ivabradine or placebo. Inclusion criteria included sinus rhythm, with a resting heart rate >70 bpm on consecutive electrocardiograms (ECGs). Persistent AF and atrial flutter were exclusion criteria. Drug dosage could be adjusted to 5 mg, 7.5 mg, or 10 mg bid, to achieve a resting heart rate of 55-60 bpm. Bradycardia was defined as heart rate <50 bpm on an ECG. The primary endpoint among patients with bradycardia was a composite of cardiovascular death or nonfatal myocardial infarction, and for AF was a composite of cardiovascular death, nonfatal myocardial infarction, and fatal or nonfatal stroke.

Results:

During a mean follow-up of 28 months, bradycardia was diagnosed in 3,572 of the 9,539 (37%) patients randomized to ivabradine. In contrast, it was diagnosed in 358 patients of the 9,544 patients (3.8%) in the placebo group. AF was diagnosed in 438 patients (4.6%) and 316 (3.3%) patients in the treatment and placebo groups, respectively (p < 0.001). AF was a new diagnosis in 74% of the patients who were diagnosed with AF. Event rates were higher in patients who developed AF in both the ivabradine and placebo groups as compared to patients without AF; however, there was no difference in outcomes among patients with AF with respect to the treatment group.

Conclusions:

Bradycardia is common among patients with CAD treated with ivabradine. Although the incidence of AF is higher in patients treated with ivabradine (2.2%/year vs. 1.5%/year in the placebo group), the event rates between the treatment groups appear to be similar.

Perspective:

Ivabradine inhibits spontaneous pacemaker activity of the sinoatrial node by blocking the If current. It has been shown to improve outcomes in patients with stable heart failure due to systolic dysfunction. It also has a role in patients with inappropriate sinus tachycardia. In the parent study (SIGNIFY), ivabradine did not improve outcomes of patients with CAD, but without clinical heart failure. The clinical significance of bradycardia is unknown since the status of the patients and their management (symptoms, pacemaker implantation, etc.) are not available. The higher rate of bradycardia in this study was likely related to the ‘aggressive’ treatment regimen, used to achieve a resting heart rate between 55-60 bpm. The current study and others have noted an increase in the incidence of AF in patients randomized to ivabradine, the mechanism of which remains unclear. It is reasonable to consider discontinuation of the drug if a patient develops AF.